Immune cell migration in inflammation: present and future therapeutic targets

The burgeoning field of leukocyte trafficking has created new and exciting opportunities in the clinic. Trafficking signals are being defined that finely control the movement of distinct subsets of immune cells into and out of specific tissues. Because the accumulation of leukocytes in tissues contributes to a wide variety of diseases, these 'molecular codes' have provided new targets for inhibiting tissue-specific inflammation, which have been confirmed in the clinic. However, immune cell migration is also critically important for the delivery of protective immune responses to tissues. Thus, the challenge for the future will be to identify the trafficking molecules that will most specifically inhibit the key subsets of cells that drive disease processes without affecting the migration and function of leukocytes required for protective immunity.     

Drug development strategies for asthma: in search of a new paradigm

The spiraling costs of asthma treatment seem set to continue rising, given the equivocal performance of the latest generation of specific anti-inflammatory drugs in trials in adult asthmatics. We argue that the continuation of this trend is inevitable unless there is a substantial realignment of entrenched drug development policy in the pharmaceutical industry and a parallel shift in licensing policy by regulatory authorities to encourage the development of drugs capable of halting the progression from acute to chronic asthma when the disease first manifests in childhood. The theoretical framework for such an approach, including proof-of-principle data from studies in children with early-stage disease and a range of candidate drugs, already exists. What is needed is informed debate on the risks versus potential benefits of this approach.     

Rapid identification of dysregulated genes in cutaneous malignant melanoma metastases using cDNA technology

One important application of DNA microarray technology is the simultaneous analysis of gene expression of different mRNAs. Comparison of mRNA patterns of diseased and healthy tissue may help to understand the pathogenesis of a given disorder. In cancer tissue, identified dysregulated genes may serve as new molecular markers for diagnosis or prognosis or may ideally serve as new targets for therapy. Using membrane cDNA array technology, we analyzed gene expression in human melanomas, one of the most aggressive types of cancer with a high metastatic potential and with markedly increased incidence worldwide. To account for the heterogeneity of tumors, we compared total RNA from cutaneous melanoma metastases of 10 different patients with primary human melanocytes. An abundance of genes was dysregulated (up-/downregulated), which involved for example the apoptosis gene growth factor receptor-bound protein 10, Bcl2-associated X membrane protein, Bcl2 antagonist of cell death, glutathione S-transferase theta(1) and glutathione reductase. Ultimately, the identification of melanoma-associated genes may provide a potential therapeutic strategy for identifying and targeting malignant melanoma.     

Comparison of GB virus C, HIV, and HCV infection markers in hemophiliacs exposed to non-inactivated or inactivated factor concentrates.

BACKGROUND: Until the mandatory introduction of viral inactivation techniques of blood plasma products in the early 1980s many recipients of these products were infected with various viral pathogens. OBJECTIVES: To determine the rate of transmission of GB virus C/hepatitis G virus (GBV-C/HGV) HCV, and HIV through non-virus-inactivated clotting factor concentrates in hemophiliacs, as well as the relation between amount of administered clotting factor and risk for GBV-C/HGV infection. STUDY DESIGN: In this cross-sectional study, we determined retrospectively the rates of infection markers for GBV-C/HGV, HCV, and HIV in a German cohort of hemophiliacs treated with documented amounts of non-virus-inactivated clotting factor concentrates (group A) and in a second group of hemophiliacs who were treated exclusively with virus-inactivated clotting factor (group B). The presence of anti-virus antibodies was determined by ELISA. Viral RNA was detected by RT-PCR. Markers for viral infections were compared to amounts of administered non-virus-inactivated clotting factor. RESULTS: Among hemophiliacs treated with documented amounts of non-virus-inactivated clotting factor the prevalence for GBV-C/HGV, HCV, and HIV was 40.3%, 98.6%, and 56.3%, respectively. In contrast to HIV, the rate of GBV-C/HGV infections did not increase with increasing amounts of consumed non-inactivated clotting factor. Even in the subgroup of heavily treated hemophiliacs the rate of GBV-C/HGV infection markers did not exceed 45%. CONCLUSIONS: The amount of non-virus-inactivated clotting factor is not predictive for the risk of GBV-C/HGV infection in hemophiliacs. Despite repeated parenteral exposure more than 55% of hemophiliacs were not infected with GBV-C/HGV. Our findings indicate a high frequency of host factors preventing parenteral transmission of GBV-C/HGV.     

Elevation of plasma viscosity induces sustained NO-mediated dilation in the hamster cremaster microcirculation in vivo

 We studied whether a flow-independent increase of luminal wall shear stress (WSS) could dilate hamster arterioles in vivo and which endothelial mediators are potentially involved. To this end the plasma viscosity was elevated by exchanging blood for dextran-erythrocyte solution thereby augmenting WSS. Diameters of small and large arterioles as well as red blood cell velocities were measured before and after exchange of blood for solutions of identical haematocrit containing either high- (HMWD) or low-molecular weight dextran (LMWD). The potential role of endothelial autacoids was investigated by local application of the NO-synthase inhibitor N ^G-nitro-L-arginine (L-NNA), the inhibitor of cyclooxygenase, indomethacin (3 μM), or the K⁺-channel blocker, tetrabutylammonium (TBA, 0.1 mM) to assess the potential effects of EDHF. HMWD (n = 11 animals) increased plasma viscosity by 64 ± 3% and dilated arterioles of all branching orders (A1–A4) significantly [by 24 ± 3% (A1–A2) and 32 ± 3% (A3–A4)]. This dilation compensated fully for the calculated initial increase of WSS. LMWD (n = 6) did not affect plasma viscosity or arteriolar diameters. Tissue treatment with L-NNA (30–300 μM, n = 12) substantially diminished the HMWD-induced dilation in small arterioles (A3–A4; to 13 ± 3%; P<0.05) and virtually abolished it in large ones (A1–A2). Consequently, the calculated WSS increased significantly in these arterioles (by 31 ± 5%). TBA combined with L-NNA (n = 4) did not reduce further the remaining dilation. Indomethacin (n = 6) had no effect on HMWD-induced dilation. We conclude that an increase of WSS induces a mainly NO-mediated arteriolar dilation. This dilation occurs in all arteriolar branching orders and is of sufficient magnitude to compensate for the initial WSS-increase. Thus, any elevations of WSS fulfil the requirement for a signal to change diameter along the arteriolar tree in a coordinated manner. The fully compensating dilation which we observed indicates that WSS is a controlled variable. It does, however, raise questions as to its role as a continuous endothelial stimulus. Received: 2 August 1996 / Received after revision: 24 February 1997 / Accepted: 14 April 1997     

Transitory subependymal cysts in the developing rat rhombencephalon

Summary A bilaterally symmetrical cystic cavity is situated in the subependymal neuropil of the rostral rhombencephalon of the rat during the perinatal period of ontogeny. These cysts are formed by the confluence of enlarged extracellular spaces in this region between E18 and E20. The cysts are present for about 2 weeks but disappear on about P15 without trace. They have a maximal volume of about 0.004 to 0.006 mm³ on P2, with a rostrocaudal extension of about 200 m. Their shape is characterized by a medial convexity and a lateral concavity, and they have their maximal circumference at about the middle of the rostrocaudal axis. The caudal portion is juxtaposed to the subependyma, while the rostral part lies in the neuropil of the presumptive griseum centrale pontis. In the lumen and the wall of the cysts are found numerous macrophages, hlioblasts and some degenerating axons and dendrites.The significance of these cysts in the context of morphogenesis and the origin of the numerous macrophages within them are both unresolved.     

Calculation of macrocyclization equilibria for poly(ethylene terephthalate)

The cyclization equilibria constant K_x is evaluated for the formation of cyclic poly(ethylene terephthalate)s (PET) in the range of degree of polymerization 2 ≤ x ≤ 10 on the basis of an elaborated form of the Jacobson-Stockmayer theory. According to this theory, K_x = W( 0 )·2Γ₀(1)/(σ_cx N_A), where W( r ) is the probability density function for the chain vector r ; Γ₀(γ) is the probability distribution, when r = 0 of γ = cos Δθ; Δθ being the deviation of the bond angle formed by cyclization from its unconstrained value; σ_cx corresponds to the symmetry number of the ring; N_A is Avogadro's number. The evaluation of W( r ) is performed in different approximations. The required configurational averages for computing the density distribution W( r ) and the angular correlation factor Γ₀(1) are obtained by Monte Carlo techniques. The density W( 0 ) of chain vectors at r = 0 is overestimated by the Gaussian approximation. Values of W( 0 ) calculated in higher approximation lower K_x for x < 10. By taking into account the oriental correlation between terminal bonds of the x-meric acyclic sequence, K_x is lowered additionally by factors of ca. 2,2, 1,3 and 1,1 for x = 4, 5 and 6, respectively. Similar to other polymer chains treated so far, K_x is lowered for medium sized chain lengths by taking into account the deviation from Gaussian distribution and angular correlations of chain ends. This result is in contradiction to experimental data, which yield even higher K_x-values than expected by the classical Jacobson-Stockmayer theory for medium sized chain lengths. The inclusion of cis-ester residues into the all trans-ester PET chain only slightly reduces this discrepancy. Structural modifications of the PET chain during cyclization experiments are discussed as a rationale for the deviations from the present theory.     

H-Y and antigens of the major histocompatibility complex.: H-Y and H-2D antigens are associated on unfixed lymphocytes and thymocytes but not on testicular cells

The results of an antibody blocking technique indicate that H-Y and H-2D antigens are close to one another on the surfaces of unfixed thymocytes and lymphocytes, but distant on testicular cells. The findings are the same using cells from mice of several inbred strains (C57BL/10, BALB/c, B6.H-2^k). The data indicate moreover that H-2K antigens and H-Y are distant on all cell types tested. The gonad specific H-Y receptor-presumed necessary for H-Y directed testicular differentiation is associated with neither H-2D nor H-2K antigens.